Diabetes and heart failure are diseases of enormous burden to Americans, and current therapies for these often-lethal diseases are clearly inadequate. The generation of organs suitable for transplantation offers tremendous potential to treat these types of diseases. The early development of over 20 mammalian organs involves the sequential, ordered exchange of signals between interacting epithelial and mesenchymal cell populations, resulting in their progressive differentiation. We hypothesize that this complex, dynamic regulatory network can be resolved by the integration of different scientific disciplines and used to design and build organ precursors or parts. As a part of the larger SysCODE consortium we will develop technologies that can be used to engineer the surrounding microenvironment. We propose to develop novel, three dimensional (3D) microscale constructs to be used as tools to study populations of interacting mesenchymal and epithelial cells . These microscale techniques will enable the biomimecry of the complex 3D structure of epithelial and mesenchymal cell interactions that occur in the embryonic in vivo environment. In vivo, the cellular environment is tightly regulated in 3D by interactions between cell-cell, cell-extracellular matrix (ECM) and cell-soluble factors. To effectively mimic mesenchymal and epithelial tissue we will engineer novel hydrogels embedded with cell types that resemble the cells native to these tissues. Addition features such as the basement membrane will also be engineered to fascilitate the movement of growth factors and environmental cues between the two types of tissue. This will all be accomplished through the successful completion of the following three Specific Aims: Aim 1: To develop biomimetic materials for engineering the cell-ECM interactions within 3D epithelial-mesenchymal constructs. Aim 2: To fabricate microscale constructs that can be used to study the interactions between epithelial and mesenchyme cell populations. Aim 3: To develop and validate a combinatorial approach to study microenvironmental factors in interacting epithelial and mesenchymal cell populations.